The efficient dispersal of an active pharmaceutical ingredient is of utmost importance in the field of respiratory medicine. In this field, it is generally desirable to employ therapeutic particles with a size (i.e. geometric diameter) in the range of 1 to 10 μm or an aerodynamic diameter of 1-5 μm in order to be delivered to the lower respiratory tract. Particles above these sizes tend to impact in the regions of the upper airways and are removed by the mucocilliary escalator.
Pulmonary drug delivery, therefore, must overcome the technical challenges of working with fine particles but still operate within the constraints dictated by human anatomy.
To facilitate delivery of cohesive powders a number of solutions have been provided in the art.
Inhaler Devices
Firstly, inhalation devices have been developed for assisting with the delivery of cohesive micronised medicament to the lungs of patients. When a patient actuates a DPI device it produce an air stream, the flow of air produced by the patient's inspiratory manoeuvre lifts the powder out of the inhaler (“Fluidisation”) and causes the separation of, inter alia, the drug from carrier (“De-agglomeration”).
Dry powder inhalers can be divided into two basic types:    i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound from a pre-metered dosage means such as a capsule or single blister tab;    ii) multidose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre-loaded with quantities of active ingredient where the drug is stored in a reservoir or blister pack/strip); each dose is created by a metering unit either within the inhaler or within the filling line prior to assembly.
On the basis of the required inspiratory flow rates (l/min) which in turn are strictly depending on their design and mechanical features, DPIs are divided in:    i) low-resistance devices (>90 l/min);    ii) medium-resistance devices (about 60 l/min);    iii) high-resistance devices (about 30 l/min).
The reported flow rates refer to the pressure drop of 4 KPa (Kilopascal) in accordance to the European Pharmacopoeia (EurPh).
For powder inhalers which release the medicament from pre-dosed units, e.g. capsules or blister packs, the same restriction applies for the low-friction operation of the filling apparatus for these unit doses. This low-friction operation is greatly improved with free flowing powder is used, for example by using large carrier particles.
Large Carrier Particles
Numerous approaches have been adopted to manipulate DPI particulate interactions. A further approach to improve the efficiency of most DPI formulations employs carrier particles as a means to overcome powder handling problems. The majority have focused on the physical properties of the carrier, specifically modifying the shape, size, or rugosity of the carrier. Other approaches have focused on producing uniform respirable drug particles by spray drying or supercritical fluid precipitation.
Lactose is the most common carrier used and can constitute more than 99% by weight of a DPI formulation. Lactose carrier particles are traditionally used as a flow aid and they assist with carrying the dose of the active into the lungs. The chemical and physical properties of lactose play an important role in DPI formulations. The selection of the specific grade of lactose is based on the inhaler device, the filling process and the required API release profile. Critically, DPI formulations need to be homogeneous however this is not the only parameter requiring consideration. The adhesion between carrier and drug particle should not be too strong because the drug will not be able to release from the lactose particle during inhalation. Likewise, it should not be so weak that the carrier separates from the carrier during routine powder handling. Furthermore, the drug should always be released from the carrier in the same way. One of the important parameters for the formulation is the particle size of the lactose.
Carrier particles or excipients, such as lactose, for inhaled therapeutic preparations also include significantly larger diameter particles (e.g. 50 to 300 μm) that typically do not penetrate into the respiratory tract to the same degree as the active ingredient.
The most common approach for describing formulations with multiple components (i.e. drug and carrier) is to use laser diffraction analysis. Machines such as the Malvern Mastersizser report results as sections namely the D10, D50, and D90 values based on a volume distribution. The D50, the median, is defined as the diameter (in microns) where half of the particle population, by volume, lies below this value. Similarly, the D90 is the value wherein 90 percent of the particle distribution, by volume, lies below the stated D90 value, and the D10 is the value below which 10 percent of the particle population resides on a volume basis.
The lactose particle size and distribution will also, in many instances, significantly influence pharmaceutical and biological properties, such as, for example, bioavailability. For example, it is well known that coarse lactose in crystalline form has a good flow rate and good physical stability whereas fine lactose powder, such as that produced by conventional fine grinding or milling, generally lacks good flow properties. Lactose prepared by conventional spray drying either lacks desired flow properties or contains too many large sized lactose crystals.
It is well known that one particular drawback associated with conventional means of producing pharmaceutical grade lactose relates to undesirable variations in particle size, morphology and distribution. Such production methods are particularly problematic in that they often lead to excessive and undesirable variations in the fine particle mass (“FPM”) of the delivered pharmaceutical active.
Lactose morphology is believed to be another important parameter to control, and it is believed that the degree of surface roughness can influence the interaction between the lactose particle and excipient and as such is now often measured as part of the lactose selection criteria.
In general, it is preferable to use smaller particle sizes for the lactose or a blend of coarse and fine particles lactose because reduction in mean particle size of the lactose has been shown to increase the aerosolisation of various drugs but this smaller size selection is marred with poor flow properties. Therefore until now the routine approach has been simply to use as few fines particles as possible.
Small Particles
Fine particles are, by their nature, cohesive, and whilst simply blending the large carrier particles, additive particles and fine excipient particles together will result in occupation of the high-energy sites on the carrier particles by additive particles, the distribution of the additive particles over these sites will be determined by the amount of energy that is used in the processing step.
One explanation for this observation is that the fine lactose particles occupy areas of high energy on the carrier surface, such as the clefts. With these high energy sites occupied by the fine lactose particles, the drug particles will then preferentially adhere to the lower adhesion sites and consequently the drug will be more easily released. A further benefit of lactose fines is the surface area increases substantially and the potential payload of each carrier also increases.
Fine particles (“Fines”) are characterized as particles with a D10 below 5 μm, D50 below 15 μm and D90 below 32 μm as determined by laser diffraction particle size analysis, for example a Spraytec with Inhalation Cell, Malvern Instruments, Malvern, UK. A balance, however, needs to be struck between desirable API detachment and premature detachment due to poor API adherence to the carrier. Whilst the presence of high lactose fines may increase the aerosol performance of a formulation, this comes at the cost of poor powder handling e.g. in conveying and filing processes.
Fine particles tend to be increasingly thermodynamically unstable as their surface area to volume ratio increases, which provides an increasing surface free energy with this decreasing particle size, and consequently increases the tendency of particles to agglomerate. The process of filling from hoppers, may result in the agglomeration of fine particles and adherence of such particles to the walls of the hoppers. This is a problem that results in the fine particles leaving the hopper as large, stable agglomerates, or being unable to leave the hopper and remaining adhered to the interior of the hopper, or even clogging or blocking the hopper. Poor flow from powder hoppers can adversely affect manufacturing operations. The uncertainty on the extent stable agglomerates formation of the particles between each dispension of the filler, and also between different hoppers and different batches of particles, leads to poor dose reproducibility. Furthermore, the formation of agglomerates means that the MMAD of the active particles can be vastly different with agglomerates of the active particles, on occasion, not reaching the required part of the lung.
As particles decrease in size, they become lighter resulting in a transition away from gravitational forces towards interparticulate forces becoming the predominate force. Conversely, as particles increase in size, they become heavier resulting in a transition away from interparticulate towards gravitational forces becoming the predominate force. Smaller particles, therefore, become overwhelmed by the forces of cohesion and adhesion which is why they adhere to one another and form agglomerates or aggregates. The likelihood of cohesion increases with decreasing particle size; particles smaller than 100 nm experience an element of cohesion. This degree of cohension increases with decreasing size.
Micronisation of the active drug is essential for deposition into the lower lungs during inhalation. As a general rule, however, the finer particles become, the stronger the forces of cohesion and/or adhesion between these particles. Strong cohesion/adhesion forces hinder the handling of the powder during the manufacturing process especially pouring and filling of powders. Moreover micronisation or the presence of micronized particles reduces the ability of the formulation to pour or flow freely under gravity (“flowability”).
The effect of non-lactose fine excipients on FPD or FPF performance of ternary formulations has also been investigated. Fines of erythritol, glucose, mannitol, polyethylene glycol 6000, sorbitol and trehalose have all been found to increase either the FPD or FPF of a variety of drugs when added. Fines of different materials have produced varying increases in formulation performance compared to each other and to lactose fines, with lactose fines producing poorer, equal and better performance in various studies.
Lactose Fines
The beneficial aerosol effects of fines on an inhaled formulation have been demonstrated through the use of pre-treatment steps in which pre-existing (intrinsic) fine particles were removed from coarse lactose carrier by either air-jet sieving or air washing lactose held on a sieve. The removal of lactose fines was found to decrease the aerosol performance of formulations containing a variety of different drugs, which were blended by different techniques and aerosolised from different inhalers. Such results are in accordance with numerous studies which, when using various grades of carrier material, different inhalers and different drug found that those containing the highest proportion of intrinsic fines gave the greatest aerosol performance (Jones & Prices, 2006).
Consequently, the majority of research in this area has focused on the addition of lactose fines to blends of coarse lactose (typically a 63-90 μm size fraction) and drug. The fine lactose typically used had a volume median diameter (VMD) of 4-7 μm and the proportion added was typically in the range 1.5 to 10%, but proportions as high as 95% have been investigated (Jones & Prices, 2006). Fine lactose in an amount as high as 95% (w/w) leads to highly cohesive formulations.
In addition to pacifying active sites, the addition of fine additive particles may also lead to the formation of fine lactose agglomerates. These lactose agglomerate particles can remain adhered to the coarse carrier lactose during processing and handling and may dramatically reduce the inspirational energy requirements in entrainment and de-aggregation of the drug particles following aerosolisation.
Despite the beneficial aerosol performance imparted by lactose fines, the addition of fines to a formulation has been found to increase device drug retention, the effect has been attributed to either the decreased flowability of powders containing a higher proportion of fine particles. The increased adhesiveness of fine particles is thought to reduce flowability of the entire powder blend in formulations containing fines contents above 10% by weight of the entire formulation. Consequently, despite the beneficial aerosol improvement, there has been a reluctance to use a fines content above 5% by weight of the entire formulation because of the poor powder flow properties of such formulations. This is because lactose fines can increase the occurrence of powder bridging in an inhaled formulation. Powder bridging is the process whereby particles in a powder bed get stuck and jam against one another creating semi-permanent structures in the powder bed. Significant time and resource is required to identify, locate and disrupt these powder bridges before powder filling can resume. Sometimes these semi-permanent structures can break apart just prior to filling into a DPI. The powder surrounding these powder bridges is often not homogeneous resulting in atypical formulation (high or low API content) entering the blisters, capsules, reservoirs of the filling line.
WO 2011 067212 discloses a fine lactose fraction. The ‘fine’ lactose fraction is defined as the fraction of lactose having a particle size of less than 7 μm, such as less than 6 μm, for example less than 5 μm. The particle size of the ‘fine’ lactose fraction may be less than 4.5 μm. The fine lactose fraction, if present, may comprise 2 to 10% by weight of the total lactose component, such as 3 to 6% by weight fine lactose, for example 4.5% by weight fine lactose.
WO 1995 011666 describes a process for modifying the surface properties of the carrier particles by dislodging any asperities in the form of small grains without substantially changing the size of the particles. Said preliminary handling of the carrier causes the micronised drug particles to be subjected to weaker interparticle adhesion forces.
EP 0 663 815 describes the addition of finer particles (<10 μm) to coarser carrier particles (>20 vim) for controlling and optimising the amount of delivered drug during the aerosolisation phase.
Lactose fines are not the only component available for manipulating the high energy sites on carrier particles and they may be used in concert with other components.
Additives (FCAs)
Co-processing of carrier particles with low surface energy materials is a further alternative for increasing the aerosolisation efficiencies of dry powder inhaler formulations.
The primary role of these low surface energy materials is to modify the interfacial properties of the carrier particles to decrease drug-carrier adhesion. Also known as Force Control Agents (“FCA”) these low surface energy materials include amino acids, phospholipids or fatty acid derivatives such as stearates, particularly magnesium stearate.
Magnesium stearate continues to be used as a tableting aide because of the stearate's glidant properties. Magnesium stearate has also been used to improve aerosol performance (Vectura), to improve resistance to moisture ingress into a formulation (Skyepharma) and to improve resistance to active degradation (Chiesi) by preventing contact with moisture.
Magnesium stearate's use in inhalable formulations leads to a general improvement in the fine particle fraction. This improvement in the inhalable fine particle fraction through the use of magnesium stearate enhances the dosing efficiency to the patient of the dry powder formulations administered by pulmonary inhalation due to an improvement of powder flowability from the dosing receptacle to the patient.
WO 2011 067212 discloses a pharmaceutical grade magnesium stearate, sourced from Peter Greven, complying with the requirements of Ph.Eur/USNF may be used as supplied with a mass median particle size of 8 to 12 μm.
WO 2011 067212 discloses magnesium stearate in a composition in an amount of about 0.2 to 2%, e.g. 0.6 to 2% or 0.5 to 1.75%, e.g. 0.6%, 0.75%, 1%, 1.25% or 1.5% w/w, based on the total weight of the composition. The magnesium stearate will typically have a particle size in the range 1 to 50 μm, and more particularly 1-20 μm, e.g. 1-10 μm. Commercial sources of magnesium stearate include Peter Greven, Covidien/Mallinckodt and FACI.
WO 87/05213 describes a carrier, comprising a conglomerate of a solid water-soluble carrier and a lubricant, preferably magnesium stearate, for improving the technological properties of the powder in such a way as to remedy to the reproducibility problems encountered after the repeated use of a high resistance inhaler device. This teaching focuses exclusively on the ability of magnesium stearate to lubricate the inhaler components.
WO 1996 23485 discloses carrier particles which are mixed with an anti-adherent or anti-friction material consisting of one or more compounds selected from amino acids (preferably leucine); phospholipids or surfactants; the amount of additive and the process of mixing are preferably chosen in such a way as to not give rise to a coating. It is stated that the presence of a discontinuous covering as opposed to a “coating” is an important and advantageous feature. The carrier particles blended with the additive are preferably subjected to the process disclosed in WO 1995 011666.
WO 2000 028979 describes the use of small amounts of magnesium stearate for improving stability to humidity of dry powder formulations for inhalation.
WO 2000 033789 describes an excipient powder for inhalable drugs comprising a coarse first fraction, a fine second fraction, and a ternary agent which may be leucine.
Kassem (London University Thesis 1990) discloses the use of relatively high amount of magnesium stearate (1.5%) for increasing the ‘respirable’ fraction. However, the reported amount is too great and reduces the mechanical stability of the mixture before use.
Glidants
The role of the tabletting glidant is to improve the flowability of the powder. This is especially important during high speed tableting production. The requirement of adequate powder flow necessitates the use of a glidant to the powder before tableting. Traditionally, talc (1-2% by weight) has been used as a glidant in tablet formulations. The most commonly used tableting glidant is colloidal silica (about 0.2% by weight) which has very small particles that adhere to the surfaces of the other ingredients and improve flow by reducing interparticulate friction. Magnesium stearate, normally used as a tableting lubricant, can also promote powder flow of the tableting powder at low concentrations (<1% by weight). Concentrations above 1% by weight tend to adversely affect powder flow performance.
Lubricants
The function of the tableting lubricant is to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. High friction during tableting can cause a series of problems, including inadequate tablet quality and may even stop production. Lubricants are thus included in almost all tablet formulations.
Tableting lubrication is achieved by either fluid lubrication or boundary lubrication. In fluid lubrication a layer of fluid (e.g. liquid paraffin) is located between the particles and die wall and thus reduces the friction.
Boundary lubrication is a surface phenomenon because the sliding surfaces are separated by a thin film of lubricant. The nature of the solid surfaces will therefore affect friction. All substances that can affect interaction between sliding surfaces can be described as boundary lubricants and in the case of tableting, they are fine particulate solids.
A number of mechanisms have been discussed for these boundary lubricants. The most effective tableting tablet boundary lubricant is magnesium stearate because of its properties. The stearic acid salts, including magnesium stearate, are normally used at low concentrations (<1% by weight) in tablet manufacture.
Besides reducing friction, lubricants may cause undesirable changes in the properties of the tablet. The presence of a lubricant in a powder is thought to interfere in a deleterious way with the bonding between the particles during compaction, and thus reduce tablet strength. Similarly, lubricants cause undesirable changes in inhaled formulations, especially with respect to reducing the desired adherence of the drug to the carrier particle. These negative effects are strongly related to the amount of lubricant present, and a minimum amount is normally used in a formulation, i.e. concentrations of 1% or below. In addition, the way in which the lubricant is mixed with the other ingredients should also be considered. The sequence, total mixing time and the mixing intensity are also important criteria.
Anti Adherent
An antiadherent reduces the adhesion between the powder and the punch faces thereby preventing particles sticking to the tableting punch. Sticking or picking is the phenomenon whereby powders are prone to adhere to the punch. This problem is associated with the moisture content of the powder; higher moisture levels aggravate the problem. The occurrence is also aggravated if the punches are engraved or embossed. Many lubricants, such as magnesium stearate, have also antiadherent properties. However, other substances with limited ability to reduce friction can also act as antiadherents, such as talc and starch.
Agglomerations
A further method of improving the flowing properties of cohesive powders is to agglomerate, in a controlled manner, the micronised particles to form spheres of relatively high density and compactness. The process is termed spheronisation while the particles formed are called pellets. The active ingredient is mixed with a plurality of fine particles of one or more excipients; the resulting product is called a soft pellet.
Generally, flow of compositions comprising fine carrier particles is poor unless they are pelletised (e.g. AstraZeneca's product OXIS (registered trademark). However pelletisation has its own disadvantages including being difficult to perform and produces variable Fine Particle Fractions (“FPF”).
The flow properties of the formulation can also be improved by controlled agglomeration of the powder. WO 2004 0117918 discloses a method of preparing a dry powder inhalation composition comprising a pharmaceutically acceptable particulate carrier, a first particulate inhalant medicament and a second particulate inhalant medicament. This application places particular importance in ensuring that any aggregates of the micronized active are broken up and the active ingredient was evenly distributed over the lactose carrier.
U.S. Pat. No. 5,518,998 discloses a therapeutic preparation comprising active compounds and a substance which enhances the absorption of the active in the lower respiratory tract, the preparation is in the form of a agglomerated dry powder suitable for inhalation.
GB 1,569,911 discloses the use of a binder to agglomerate a drug into soft pellets, which is extruded through a sieve to create agglomerates. The formation of soft pellets allows carrier particles to be omitted from the composition. U.S. Pat. No. 4,161,516 also discloses the formation of soft drug pellets to improve powder flow. U.S. Pat. No. 6,371,171 discloses spheronised agglomerates that are able to withstand processing and packaging but de-agglomerate into primary particles during inhalation.
EP 441740 discloses a process and apparatus for agglomerating and metering non-flowable powders preferably constituted of micronised formoterol fumarate and fine particles of lactose (soft pellets). Furthermore several methods of the prior art were generally addressed at improving the flowability of powders for inhalation and/or reducing the adhesion between the drug particles and the carrier particles.
GB 1 242 211, GB 1 381 872 and GB 1 571 629 disclose pharmaceutical powders for the inhalation in which the micronised drug (0.01-10 μm) is respectively mixed with carrier particles of sizes 30 to 80 μm, 80 to 150 μm, and less than 400 μm wherein at least 50% by weight of which is above 30 μm.
The prior art discloses several approaches for improving the flowability properties and the respiratory performances of low strength active ingredients. WO 1998 031353 claims a dry powder composition comprising formoterol and a carrier substance, both of which are in finely divided form wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml. Said formulation is in the form of soft pellet and does not contain any additive.
Whilst the matter of improved aerosol performance appears has been adequately addressed by industry. There is still, however, a need for inhalable powders having improved dispersion of the API whilst maintaining superior handling and powder flow characteristics.
Poorly Flowing Powders
In multidose DPIs, cohesive/adhesive particulates impair the loading of the powder from a chamber, thereby creating handling and metering problems.
Poor flowability is also detrimental to the respirable fraction of the delivered dose because the active particles are unable to leave the inhaler. The active particles in a poor flowing powder are either adhered to the interior of the inhaler and/or they leave the inhaler as large agglomerates. Agglomerated particles generally cannot reach the bronchiolar and alveolar sites of the lungs because they are too large and impact in the oralpharyngeal cavity or upper airways. The extent of particulate agglomeration between each actuation of the inhaler and also between inhalers and different batches of particles, leads to poor dose reproducibility making these products unsuitable for patient use.
In this regard, it is well known that the interparticulate forces may be too high and prevent the separation of the micronised drug particles from the surface of the coarse carrier during inhalation. The surface of the carrier particles is, indeed, not smooth but has asperities and clefts, which are high energy sites on which the active particles are preferably attracted to and adhere more strongly.
In consideration of all problems and disadvantages associated with respect to the use of fine lactose, it would be highly advantageous to provide a formulation capable of delivering active ingredients using a DPI device that has excellent flowability.
The Carr index is used in pharmaceutics as a powder flow indicator. A Carr index greater than 25 is considered to be an indication of poorly flowing powder, and below 15, of acceptable flowability.
The Carr index is related to the Hausner ratio, another indication of flowability.
Packaging Lines
The efficiency and profitability of an inhaled product depends on the type of pack and the material selected for the chosen production line. For example, the filling speed for an inhaled formulation will depend on its characteristics: the dosing size, flowability, the propensity of the formulation to segregate, as well as the receptacle into which the powder will be dispensed. For a non-fragile easy-flowing powder, filling speeds for capsules are normally less than 300 000 doses per hour, with 3000 doses per minute for a blister strip (assuming 60 doses per strip and 50 strips per minute) and approximately 3000 doses per minute for a blister pack. Choosing a poorly flowing powder irrespective of the receptacle used could reduce the filling speed to well below these values, severely impacting on the commercial success.
Tablets and inhaled formulations require the ability to be confined into a predetermined space i.e. the filling machine. Tableting, however, requires that the dosage form remain intact and compact following pressing and dispensing into the receptacle. Inhalation, in contrast, presents a completely different technical challenge in that the dosage form is required to withstand a small amount of compaction to assist dispensing of the powder plug from the filling apparatus into the receptacle. Following dispensing into a receptacle this plug must then disintegrate otherwise the powder is not presented in an inhalable form. This dosage form elasticity required by inhaled formulations presents a significant challenge not yet solved in the art, especially when higher fines contents are used.
Acceptable aerosol performance is a crucial parameter for an inhaled formulations and a parameter that is routinely focused on by formulators. However, a formulation that does not readily and reproducible fill into a receptacle does not constitute commercially viable product.
In none of aforementioned documents have the features of the invention been disclosed nor do any of them contemplate the problem or contribute or to the solution of the problem according to the invention.
All the attempts at obtaining stable powder formulations with low strength active ingredients endowed with good flowability and high fine particle fraction according to the teaching of the prior art were unsuccessful as demonstrated by either the prior art or the control examples reported below. In particular, the prior art reports that the proposed solutions for a technical problem (i.e. improving dispersion of the drug particles) was detrimental to other parameters (e.g. improving flowability, mechanical stability) or vice versa.